Basic thienylalkanes for increasing blood flow

ABSTRACT

COMPOUNDS HAVING THE FORMULA   THIENYL-CH(-AR)-CH(-R1)-CH(-R2)-N(-R3)-C(-R4)(-R5)-CH(-R6)   -(R7,R8-PHENYL)   WHERE THE THIENYL GROUP CAN BE SUBSTITUTTED BY ONE OR MORE LOWER ALKYL GROUPS, AR IS A THIENYL OR PHENYL GROUP WHICH CAN BE SUBSTITUTED BY ONE OR MORE LOWER ALKYL OR LOWER ALKOXY GROUPS, R1, R2, R3, R4 AND R5 ARE HYDROGEN OR LOWER ALKYL, R6 IS HYDROGEN OR HYDROXYL AND R7 AND R8 ARE THE SAME OR DIFFERENT AND ARE HYDROGEN, HYDROXYL, HALOGEN, LOWER ALKYL, LOWER HALOALKYL OR LOWER ALKOXY AND THEIR SALTS ARE USEFUL IN HEART AND CIRCULATORY ILLNESSES.

United StatesPatent Ofice Patented July 30, 1974 Int. Cl. A61k 27/00 US.Cl. 424-275 15 Claims ABSTRACT OF THE DISCLOSURE Compounds having theformula where the thienyl group can be substituted by one or more loweralkyl groups, Ar is a thienyl or phenyl group which can be substitutedby one or more lower alkyl or lower alkoxy groups, R R R R and R arehydrogen or lower alkyl, R is hydrogen or hydroxyl and R and R are thesame or different and are hydrogen, hydroxyl, halogen, lower alkyl,lower haloalkyl or lower alkoxy and their salts are useful in heart andcirculatory illnesses.

This is a division of application Ser. No. 182,192, filed Sept. 20,1971, now Pat. 3,767,675, issued Oct. 23, 1973.

The present invention is directed to new compounds of the formula CH-Aras R1 3 dH-oH-N-o-ci1 I I I 1 R1 R3 R3 R4 Ra a where the thienyl groupis unsubstituted or is substituted by one or more lower alkyl groups, Aris a thienyl or phenyl group which is unsubstituted or is substituted byone or more lower alkyl or lower alkoxy groups, R R R R and R arehydrogen or lower alkyl, R is hydrogen or hydroxyl and R and R are thesame or different and are hydrogen, hydroxyl, halogen, lower alkyl,lower haloalkyl or lower alkoxy and their salts, especially theirpharmacologically acceptable salts. The compounds also exist inoptically active or diastereomeric forms. The alkyl, haloalkyl andalkoxy groups have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.Of the halogen atoms fluorine, chlorine and bromine can be mentioned. Anexample of a haloalkyl group is the trifluoromethyl group. The alkylgroups are preferably straight chain.

The compounds of the invention are pharmacologically active, especiallyin circulatory illnesses. They increase the peripheral and cerebralblood flow and are therefore suited to raise the cerebal and muscleblood flow. Besides they cause a widening of coronary vessels. They areuseful in human or veterniar'y medicine, e.g. in treating dogs and cats.

The compounds of the invention, particularly in the form of their salts,also can be used to cure melamineformaldehyde resins.

The production of the compounds of the invention can be carired out, forexample, if there is reacted in known manner a compound of the formula(or a salt of such compound) 7 a h 4 I s Ra II where AB'R has thestructure C=CR or R1: R2: R3 R4: R5: :R61 R7 and R8 being as definedabove, with a reducing agent, in a given case in the presence of adehydrating agent. Many of the compounds of formula II are disclosed inThiele et al. application 80,456 filed Oct. 13, 1970 and Thiele et al.Pat. 3,330,825. The remainder can be prepared by the method disclosed inthe Thiele application and Thiele patent. The entire disclosure of theThiele et al. application and Thiele et al. patent are herebyincorporated by reference.

In the production of compounds of Formula II frequently there isobtained a mixture of the tertiary alcohol (A-BR is C(OH)CHR and thecorresponding unsaturated compound (A'BR is C=CR This type of mixturecan likewise be used for the production of compounds of formula Iaccording to the above-stated process.

The reduction can be carried out, for example, with hydrogen in thepresence of hydrogenation catalysts, suitably in a solvent such asalcohols, e.g. ethyl alcohol,, methyl alcohol or isopropyl alcohol,dioxane, benzene, acetic acid, ethyl acetate, etc. As hydrogenationcatalysts noble metal catalysts such as palladium, rhenium, platinum,etc. or catalytic sulfides such as palladium sulfide, platinum sulfide,rhenium heptasulfide and the like. The catalysts can be used with orwithout carriers. As carriers there can be used for example bariumsulfate, aluminum oxide, silica gel, etc. The hydrogenation is carriedout conveniently at temperatures between 20 and C. at normal or elevatedpressures, for example up to 100 atmospheres absolute. Preferably thepressure is between 2 and 20 atmospheres.

Furthermore as the reducing agent there can be used nascent hydrogen,for example metallic sodium in a lower alcohol, e.g. methanol, ethanolor propanol, with or without the addition of water, sodium in liquidammonia, sodium amalgam in the presence of an acid such as dilutehydrochloric acid, dilute sulfuric acid or acetic acid. The reaction canbe carried out in general at room temperature or elevated temperature upto about C.

Furthermore, for example, it is also possible to carry out the reductionelectrolytically or with other hydrogen forming agents such as complexmetal h'ydrides, for example alkaliborohydrides, e.g. sodiumborohydride, lithium alanate, sodium bis (2-rnethoxyethoxy)-aluminumhydride in the presence of hydrogenation catalysts.

If there is present as the starting materials compounds of formula II inwhich -ABR has the structure C(OH)CHR it is frequently recomended tosimultaneously add dehydrating materials. As dehydrating agents therecan be used, for example, mineral acids such as sulfuric acid orhydrohalic acids, e.g. hydrochloric acid, hydrobromic acid andhydroiodic acid, organic acids such as oxalic acid, formic acid,p-toluene sulfonic'acid) thionyl chloride, aluminum chloride, zincchloride, tin chloride, boron trifluoride, potassium hydrogen sulfate,aluminum oxide, phosphorus pentoxide and acid chlorides, e.g. acetylchloride. Especially preferred as the reducing agent is nascent hydrogenin an acid medium.

of hydrochloric acid, maleic acid, malonic acid, acetic acid,

lactic acid, fumaric acid, hydrobromic acid, succinic acid, p-toluenesulfonic acid, sulfuric acid, citric acid, etc.

Those compounds which contain asymmetric carbon atoms and as a ruleprecipitate as racemats can in known way, for example, by means ofoptically active acids, be split into the optically active isomers.However, it is also possible from the outset to use optically active ordiasteromer starting materials whereby there is obtained in the finalproduct a correspondingly pure optically active form or diastereomerconfiguration.

The production of starting materials of formula II can be carried out,for example, if there is reacted in known manner a compound of theformula 112 R7 W-r su i R1 R R R5 R5 R5 111 where Y is chlorine,bromine, an alkoxy group, the Ar group or a thienyl group and where Rthrough R, are as defined above with the corresponding thienyl or phenylmetal compound (for example lithium or Grignard compounds, e.g. thienyllithium, phenyl lithium, thienyl magnesium chloride, thienyl magnesiumbromide, phenyl magnesium chloride and phenyl magnesium bromide), in agiven case in excess in inert solvents such as dialkyl ethers, e.g.diethyl ether, tetrahydrofuran, hydrocarbons, e.g. benzene, etc. at atemperature between -l C. and +100 C. When thienyl(3) metal compoundsare reacted the reaction goes most favorably below 40 C., for example at70 C.

If compounds are obtained thereby in which the group ABR is the groupC(OH)CHR then these can in a given case be converted with watersplitting agents into the corresponding unsaturated compounds having thegroup C=CR The splitting out of water is carried out suitably atelevated temperatures, for example in the temperature range of 20 to 150C. Preferably solvents are used as, for example, glacial acetic acid,benzene dioxane, etc. As agents for splitting out water there can beused, for example, mineral acids such as sulfuric acid or hydrohalicacids, e.g. hydrochloric acid and hydrobromic acid, organic acids suchas oxalic acid, formic acid and ptoluene sulfonic acid, thionylchloride, aluminum chloride, zinc chloride, stannic chloride, borontrifluoride, potassium hydrogen sulfate, aluminum oxide, phosphoruspentoxide, acid chlorides, e.g. acetyl chloride, and redphosphorus-liodine in the presence of water.

Examples of preferred compounds within formula I are:

(a) Compounds of formula 1 wherein the thienyl group is unsubstitutedand linked in the 2- or 3- position, Ar is an unsubstituted phenyl orthienyl-(2)- or thienyl-(3)- group, R is hydrogen or an alkyl grouphaving 1 to 3 carbon atoms, preferably methyl, R R R R and R arehydrogen, R is an alkyl group having 1 to 3 carbon atoms, preferablymethyl, and R is a hydroxyl group.

(b) Compounds as set forth in (a) wherein the thienyl group issubstituted once or twice, preferably in the alpha position, by an alkylgroup, especially methyl, in case Ar is a phenyl group this can besubstituted once or twice by a straight or branched chain alkyl grouphaving 1 to 4 carbon atoms and R, can be a straight or branched chainalkyl group having 1 to 6 carbon atoms, especially methyl, or a halogenatom such as fluorine, chlorine or bromine, preferably chlorine, or analkoxy group, preferably methoxy.

(c) Compounds as set forth in (a) and (b) wherein at least one thienylgroup is linked in the 3- position.

The compounds of the invention are suited for the production ofpharmaceutical compositions and preparations. The pharmaceuticalcompositions or medicines contain one or more of the compounds of theinvention as active ingredients, in a given case in admixture with otherpharmacologically active materials. The production of the medicines canbe accomplished with the use of known and customary pharmaceuticalcarriers and additives.

The medicines can be employed enterally, parenterally, orally,perlingually or in the form of sprays.

Suitable carriers and assistants are shown for example in UlmannsEncyklopadie der Technischen Chemie, Vol. 4 (1953), pages 1 to 39;Journal of Pharmaceutical Sciences, Vol. 52 (1963), pages 918 andfollowing, H.v. Czetsch-Lindenwald, Hilfstoffe fur Pharmazie andangrenzende Gebiete, as well as in Pharm. Ind., Vol. 2, 1961, page 72and following. The entire disclosure of these publications are herebyincorporated by reference.

Examples of such carriers and assistants are gelatin, sucrose, pectin,starch, methylcellulose, talcum, lycopodium, silica, lactose, cellulosederivatives, glucose, fructose, stearates, emulsifiers, plant oils,water, pharmaceutically compatible mono or polyvalent alcohols andpolyethylene glycols such as ethyl alcohol, diethylene glycol,polyethylene glycol 400, ethylene glycol, propylene glycol, glycerine,sorbitol, mannitol, pentaerythritol as well as derivatives of suchalcohols, dimethyl sulfoxide, esters of aliphatic saturated orunsaturated fatty acids, e.g. stearic acid, palmitic acid or oleic acidwith mono or polyvalent alcohols such as glycols, e.g. ethylene glycol,glycerine, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc.,which in a given case can be etherified, benzyl benzoate, dioxolane,glycerine formal, glycolfurole, dimethyl acetamide, lactamide, ethyllactate, ethyl carbonate, etc.

It is also possible to add preservatives, buffers, taste correctives,antioxidants and complex formers (for example, ethylenediaminetetraceticacid) and the like.

As antioxidants there can be used, for example, sodium meta bisulfite,and ascorbic acid, as preservatives, for example, sorbic acid, ethylester of p-hydroxy-benzoic acid and similar materials.

The pharmaceutical preparations generally contain 1 to 50% of the activecomponent of the invention, but as stated above can contain of theactive material.

Dispensing as indicated above can be in the form of tablets, capsules,pills, drages, plugs, liquids or aerosols. As liquids there can be usedoily or aqueous solutions or suspensions. Preferred form of use are astablets containing 10 to 100 mg. of active material or as solutions,e.g. aqueous solutions containing 0.2 to 2% of active materials.

The amount of the active component of the invention in the individualdosages, for example in dispensing orally is 30 mg., in dispensingintravenously 5 mg., always calculated on the free base. These dosagescan be dispensed once or several times daily.

For example, 1 to 3 tablets containing 30 mg. of active material can bedispensed daily or, for example, a 2 ml. ampoule containing 5 mg. ofactive substance can be injected intravenously 1 to 3 times a day.

The compounds of the invention can be administered to mammals such ashumans, dogs, cats, cattle, sheep, rats, mice, etc.

The acute toxicity of the compounds of the invention in mice (expressedas the LD in mg./ kg.) in oral application for example is for example1200 mg./ kg. (or above 500 mg./kg.).

The compounds of the invention when measuring the blood flow with anelectromagnetic flowmeter in the vertebralis artery (cerebral) andfemoralis artery (peripheral) on narcotized dogs show a good increase inthe cerebral and peripheral blood flow.

The increase in cerebral and peripheral blood flow is comparable withthe activity of the known medicine 3-hydroxymethyl pyridine.

The lowest effective dosage in the animal experiments set forth above,for example, is 5 mg./kg. orally and 0.1 mg./kg. intravenously.

As general dosage ranges for activity (based on the above animalexperiments) there can be used 5-30 mg./ kg. orally and 0.1-1 mg./kg.intravenously.

The compounds of the invention are useful in circulatory disturbances ofvarious genesis, peripheral and cerebral blood disturbances, migraine,arteriosclerosis, Raynauds disease, Ulcus cruris, Studeokish syndrome,encephalo malacia.

The compounds of the invention tested on isolated guinea pig heartfollowing the method of Langendorff (Pflugers Arch. 61, 291 (1895),showed a good increase in coronary blood flow.

This activity is comparable with that of the known agent papaverine.

As general dosage range for the activity in the abovementionedexperiments there can be used 5 to 500 g/ heart.

The compounds of the invention are indicated for use in coronaryinsufliciency, angina pectoris and myocaridc infarct.

The dosage for humans generally is in the range of 1 to 100 mg. ofactive material one or more times a day.

Unless otherwise indicated all parts and percentages are by weight.

EXAMPLE 1 l [1,1- dithienyl 3 propyl (3)] [1 phenyl 1- hydroxypropyl-(2) ]-amine 1 L L P mps-Q Hr-CHrNH-(FH 20 grams of1-[1,1-dithienyl-(3)-propen-(1)-yl-(3)]-[1-phenyl-l-hydroxypropyl-(Z)]-amine were suspended in 250 ml. of ethanoland hydrogenated at room temperature at 5 atmospheres absolute hydrogenpressure in the presence of 40 grams of 5% palladium/barium sulfateuntil the calculated amount of hydrogen was taken up, whereby thematerial went into solution. After filtering ofi the catalyst thesolution was distilled. The base remaining behind (M.P. 94 C.) wasdissolved in hot acetone, filtered and converted into the hydrochloridewith isopropanolic HCl which was recrystallized from ethanol. M.P. 237C., yield 5 grams.

The starting material was produced as follows:

The 3-thienyl lithium solution was prepared from 16 grams (0.25 mol) ofn-butyllithium in 167 ml. of nhexane and 40.7 grams (0.25 mol) of3-bromo-thiophene at -70 C. To this solution there was added 25.1 grams0.1 mol) of l-fi-[l-phenyl-l-hydroxypropyl-(2)-amino]- propionic acidethyl ester in 100 ml. of absolute ether and held at -70 C. for 30minutes. After gradually warming to C. it was decomposed with 100 ml. ofwater, the organic phase separated, dried with potassium carbonate,filtered and neutralized with isopropanolic HCl. The 1-[ 1,1-dithienyl-(3 -1-hydroxypropyl- (3 1-[ 1- phenyLI-hydroxypropyl-(2)]-amine. HCl in100 ml. of chloroform was treated with HCl gas until the entire materialwent into solution. The solvent was distilled off, the residue treatedwith 10% soda lye, the base taken up in ether and neunalized withisopropanolic HCl. The base was set free from the1-[1,1-dithienyl-(3)-propen-(1)-yl- (3 )-l-[l-phenyl-l-hydroxypropyl-(Z) ]-amine. HCl (M.P. 225 C.) by treating itwith 20% soda lye and the base was recrystallized from isopropanol, M.P.124 C.

6 EXAMPLE 2 1- l, l-dithienyl- (2) -propyl- (3)-]-[1-phenyl-l-hydroxypropyl- (2) ]-amine The base was set free as anoil from 13 grams of 1 [1,1 dithienyl(2)-l-hydroxypropyl-(3)-][l-phenyl-lhydroxy-propyl-(2)]-amine maleate bytreatment with 20% soda lye and hydrogenated in 200 ml. of ethanol inthe presence of 10 grams of 10% palladium/barium sulfate at roomtemperature and 6 atmospheres absolute hydrogen pressure. The solutionwas filtered, the solvent distilled off, the base remaining behind (M.P.198 C.) dissolved in acetone/ ethanol (1 :1 by volume) and convertedinto the hydrochloride with isopropanolic HCl. It had a melting point of201 C. after recrystallization from isopropanol, yield 4 grams. In orderto form the starting material 1 mol of 1 B [l-phenyl-1-hydroxypropyl-(2)- amino]-propionic acid ethyl ester reacted with 2mols of Z-thienyl magnesium bromide in ether at the boiling point. Afterdecomposition with aqueous ammonium chloride solution the oily base wasobtained which was converted by maleic acid to the maleate in ether,M.P. 137138 C.

EXAMPLE 3 1- l-thienyl- 2) -l-thienyl- (3 )-propyl- (3 [phenyl-1-hydroxypropyl-(Z) ]-amine u U. 8/ t -Q The base (M.P. 86 C.) was setfree from 14 grams of 1[1-thienyl-(2)-1-thienyl-(3)-propen-(1)-yl-(3)]-[1-phenyl-l-hydroxypropyl-(Z)-]-amine. HCl by treatment with 20% soda lyeand hydrogenated in 300 ml. of ethanol in the presence of 40 grams of 5%palladium/ barium sulfate at 20 C. and 6 atmospheres absolute hydrogenpressure. The solution was filtered and the solvent distilled oif. Thebase remaining behind (M.P. 82 C.) was dissolved in boiling acetone andconverted into the hydrochloride with isopropanolic HCl. Thehydrochloride was recrystallized from isopropanol, M.P. 231 C yield 6grams.

In order to form the starting material l-p-[l-phenyl-lhydroxy-propyl(2)-amino]-propiothienone-(3) was reacted with 2-thienyl magnesiumbromide in ether at the boiling point. After decomposition with aqueousammonium chloride solution there was obtained 1-[l-thienyl-(2)-l-thienyl (3) 1 hydroxypropyl-(3)]-[1-phenyl-1-hydroxypropyl-(Z) ]-aminethat was converted by treatment with HCl gas into the above-employedhydrochloride (M.P. 206-207 C.)

EXAMPLE 4 1- l-thienyl- 3 l-phenylpropyl- (3 l-phenyl- 1- hydroxypropyl-(2) -amine UTHQ (OE OHS PCHPNH- The free base (as an oil) was set freefrom 10 grams of 1 [lthienyl-(3)-1-phenyll-hydroxypropyl-(3)]-[lphenyl-l-hydroxypropyl-(Z)]amine. H Cl by treatment with 20% soda lye and hydrogenated in ml. ofethanol in the presence of 20 grams of 5% palladium/ barium sulfate at20 C. and atmospheres absolute hydrogen pressure. The solution wasfiltered, the solvent distilled off, the base (oil) remaining behinddissolved in acetone and converted into the hydrochloridewith'isopropanolic HCl. After recrystallization from isopropanol it hada melting point of 228 C., yield 2 grams.

In order to form the starting material l-fi-[l-phenyl-lhydroxypropyl(2)-arnino]propiothienone-(3) was reacted with phenyl magnesium bromidein ether at the boiling point. The oily base obtained afterdecomposition with aqueous ammonium chloride solution was converted intothe hydrochloride (M.P. 214-215 C.) with isopropanolic HCl.

EXAMPLE 5 1- l-thienyl- (2) l-phenylpropyl- 3) l-phenyl- 1-hydroxypropyl- (2) ]-amine The base (M.P. 112 C.) set free from grams of1- [l-thienyl-(Z) -1- phenyl propen (1) yl (3)]- [1 phenyl 1 hydroxypropyl (2)] amine. HCl by treatment with soda lye was hydrogenated in200 ml. of ethanol in the presence of 8 grams of 10% palladium/bariumsulfate at 20 C. and 6 atmospheres absolute hydrogen pressure. Thesolution was filtered and the solvent distilled off. The base remainingbehind (M.P. 227 C.) was dissolved in a boiling acetone-ethanol mixture(2:1 by volume) and converted into the hydrochloride with isopropanolicHCl. After recrystallization from isopropanol the hydrochloride had amelting point of 231 C., yield 3 grams.

EXAMPLE 6 d,l-[ l-phenyll-thienyl- (2 -propy1- 3 1-(4-chloropheny1)-propyl-(2) ]-amine The free base (oil) was set freefrom 20 grams of d,l- [l phenyl-1-thienyl-(2)- propen (1) yl (3)]- [1 (4chlorophenyl) propyl (2)] amine. E01 by treatment with 20% soda lye andhydrogenated in 300 ml. of ethanol in the presence of 40 grams of 5%palladium/ barium sulfate at 20 C., and 6 atmospheres absolute hydrogenpressure. After filtering the solution and distilling off the solventthe base (M.P. 186 C.) was obtained which was dissolved in boilingacetone and converted to the hydrochloride with isopropanolic HCl. Thehydrochloride had a melting point of 202 C. after recrystallization fromisopropanol, yield 5 grams.

EXAMPLE 7 d,l-[ 1,1-dithienyl-(3 )-propyl(3 1-phenyl-1- hydroxypropyl-(2) ]-amine l li W 8 i s on on CH:rCHaNH- H H3 10 grams ofd,l-[1,1-dithienyl-(3)-1-hydroxypropyl-(3)]-[l-phenyl-1-hydroxypropyl-(2)]-amine were hydrogenated in 300 ml.of ethyl acetate in the presence of 10 grams of 10% palladium/bariumsulfate at 45 C. and 6 atmospheres absolute hydrogen pressure. Thesolution was filtered and neutralized with isopropanolic HCl, whereuponthe HCl salt precipitated. It had a melting point of 203-204 C. afterrecrystallization from isopropanol,

yield 5 grams.

EXAMPLE 8 d,l-[1,1-dithienyl-(3)-propyl-(3)]-[1-(4-fluorophenyl)-l-hydroxypropyl- 2) ]-amine 3 grams ofd,l-[1,1-dithienyl-(3)-propen-(1)-yl-(3)]-[1-(4-fluorophenyl)-1-hydroxypropyl-(2) ]-amine. HCl in 50 ml. ofethanol were hydrogenated in the presence of 0.5 grams of 10%palladium/activated carbon at 70 C. and 6 atmospheres absolute hydrogenpressure. The hot reaction solution was filtered off from the catalystand the solvent distilled off. The HCl salt remaining behind wasrecrystallized from ethanol, M.P. 216218 C., yield 2 grams.

The starting material was produced in the manner described in example 1from d,l-,8[1-(4-fluorophenyl)-1- hydroxypropyl-(2)-amina]-propionicacid ethyl ester and B-thienyllithium, M.P. 206 C.

In addition to the compounds mentioned in the specific examples aboveillustrative of other compounds within the invention that can beprepared in similar fashion are 1-[1,1-di(2-methylthienyl)-(3)-propyl]-[1-phenyl-1- hydroxypropyl-( 2) ]-amine,d,l-[1-(5-isopropyl)-thienyl- (2) 1-thienyl-(3)-propyl-(3)]-[1-phenyl 1hydroxypropyl-(2)]-amine), 1-[1,-di(2,5-dimethylthienyl) (3)-propyl]-[l-p-tolyl-l-hydroxypropyl-(Z)] amine, 1 [1-thienyl-(2)-1-p-tolyl-propyl-(3)]-[ l-m-xylyl 1hydroxypropyl-(2)]-amine, 1-[1,1-dithienyl (2) (2-methyl)-propyl-(3)1-[1-phenyl-1 hydroxypropyl (2)]amine, 1-[1,1-dithienyl-(3)-(2)-propyl)-propyl (3)] [1 (2-bromophenyl)-pr0pyl-(2)]-arr1ine, 1-[1,1-dithienyl (3)-propyl-(3)]-[l-phenyl-l-hydroxyamyl-(2)] amine, d,l-[1,1-dithienyl-(2)-propyl-(3)]-[1 phenyl 1 hydroxyethyl-(2)]-amine,1-[1,1-dithienyl-(3)-propyl-(3)] [1-phenyl-l-hydroxypropyl-(2)]-N-methylamine, d,l-[lpmethoxyphenyl)-1-thienyl-(3)-propyl (3)] [1 4 hydroxyphenyl)-1-1hydroxypropyl-( 2) ]-amine, d,l-[1-(2)- sec.butyl-l-thienyl-(Z)-propyl-(3)] [1 (4 methoxyphenyl)-propyl(2)]-amine,1-[1,1-dithienyl-(3) propyl- (3)]-[1-(4-hexylphenyl)-propyl-(2)] amine,d,l, [1,1- dithienyl-( 2) -propyl-( 3 1 (4-trifiuoromethylphenyl)-l-hydroxy-propyl-(Z)]-amine, 1 [1,1 dithienyl (3)-propyl-(3)]-[1-(2,4-dimethylphenyl)-1 hydroxypropyl- (2) [-amine,1-[1,1-dithienyl-(3)-propyl-(3)l [1 (2,4-dihydroxyphenyl)-1-hydroxypropyl (2)] amine, d,l-[l-phenyl-l-thienyl-(2)-propyl (3)] [1(3-hydroxyphenyl)-propyl-(2)]-amine, 1-[1,1-dithienyl (2)-propyl-(3)]-[1-(4-isobutylphenyl) 1 hydroxypropyl (2)]- amine.

The compounds of the invention can be administered to mammals such ashumans, dogs, cats, cattle, sheep, rats, mice, etc.

Following are examples which illustrate the production of pharmaceuticalpreparations.

EXAMPLE 9 Production of an Injectable Solution 10 grams of1[1-thienyl-(2)-1-thienyl-(3 )-propyl-(3) [l-phenyl-l-hydroxypropyl (2)]amine hydrochloride were dissolved in the cold in a mixture of 200 gramsof 96% ethanol and 800 grams of 1,2-propylene glycol. The solution wasdiluted with Water to 2000 ml. for injection, passed through a bacteriadestroying filter and filled into 2 ml. glass ampoules in known manner.

The production of the injectable solution takes place under sterileconditions. It is also possible to work under normal conditions and thento heat sterilize the filled ampoules. Each 2 ml. ampoule contained mg.of the active material.

EXAMPLE 10 Production of an Injectable Solution 5.0 grams of1-[1,1-dithienyl-(3)-propyl-(3)]-[lphenyl-l-hydroxypropyl-(2)]-aminehydrochloride were dissolved in the cold in a mixture of 200 grams of96% ethanol and 600 grams of 1,2-propylene glycol. The solution wasdiluted with water to 1000 ml. for injection, passed through a baceteriadestroying filter and filled into 2 m1. glass ampoules in known manner.

The production of the injectable solution takes place under sterileprecautions. It is also possible to operate, under normal conditions andto heat sterilize the filled ampoules. Each 2 ml. ampoule contains 10mg. of the active material.

EXAMPLE 11 Production of Suppositories 25 grams ofd,l-[1,1-dithienyl-(3)-propyl-(3)]-[1- phenyl-1-hydroxypropyl(2)]-aminehydrochloride were worked into 1975 grams of a melted suppository mass,for example Hartfett DAB 7 (a hard fat which is a mixture of primarilysaturated higher ,fatty acid glycerides) and in known manner poured intoforms to make 2.0 gram suppositories. Each suppository contained 25 mg.of

active material.

EXAMPLE 12 Produciton of Tablets EXAMPLE 13 Production of Gelatin StickCapsules 250 grams of d,l-[1,1-dithienyl-(3')-propyl-(3)]- [1-phenyl1hydroxypropyl-(2)]-amine hydrochloride were mixed with 250 grams ofmannitol and granulated with 125 ml. of 96% ethanol, after drying passedthrough a 0.5 mm. mesh sieve and filled into gelatin stick capsules inindividual amounts of 250 mg. As single dosages 1 to 2 capsulescorresponding to 125 to 250 mg. of active material can be taken.

What is claimed is:

1. A sterile, nontoxic, pharmaceutical composition useful for increasingblood flow in a mammal comprising a pharmaceutical carrier and as theactive ingredient in an amount effective to increase blood flow, acompound having the formula wherein the thienyl group is eitherunsubstituted or substituted by at least one lower alkyl group, Ar is athienyl or phenyl group which is unsubstituted or substituted with atleast one lower alkyl or lower alkoxy group, R R R R and R are hydrogenor lower alkyl, R; is a hydroxyl group, and R and R are the same ordifferent and are hydrogen, hydroxyl, halogen, lower alkyl, lowerhaloalkyl or lower alkoxy or a pharmacologically acceptable salt of suchcompound.

2. The composition of claim 1 containing 1 to 50% of said activeingredient in a pharmaceutically acceptable carrier.

3. The composition of claim 1 in the form of a solid pill, tablet orcapsule.

4. The composition of claim 1 in the form of an injectable solution ofthe active ingredient in a nontoxic solvent.

5. The composition of claim 4 wherein the solution is in an ampoule.

6. The composition of claim 4 wherein the solvent includes a glycol.

7. The composition of claim 1 including a sugar.

8. The composition of claim 1 wherein the first mentioned thienyl groupis unsubstituted, Ar is unsubstituted phenyl or thienyl, R is hydrogenor alkyl of 1 to 3 carbon atoms, R R R R and R are hydrogen, R is alkylof 1 to 3 carbon atoms and R is hydroxyl.

9. The composition of claim 8 wherein R is hydrogen or methyl and R ismethyl.

10. The composition of claim 9 wherein at least one thienyl group islinked in the 3- position.

1'1. The composition of claim 1 wherein the firstmentioned thienyl groupis unsubstituted or has one or two methyl groups, Ar is phenyl havingone to two alkyl groups of 1 to 4 carbon atoms or is thienyl, R ishydrogen or alkyl of 1 to 3 carbon atoms, R R R and R are hydrogen, R isalkyl of 1 to 3 carbon atoms, R is hydroxyl and R is alkyl of 1 to 6carbon atoms, fluorine or chlorine, or methoxy.

12. The composition of claim 11 wherein any alkyl group present in thecompound is methyl and any methyl group attached to a thienyl group inthe alpha position and R- is methyl, chlorine or methoxy.

13. The composition of claim 12 wherein at least one thienyl group islinked in the 3- position.

14. The composition of claim 1 wherein the firstmentioned thienyl groupis unsubstituted, Ar is unsub stituted thienyl or phenyl, R R R R R andR are hydrogen, R is methyl and R is hydroxyl.

15. The composition of claim 1 wherein the firstmentioned thienyl groupis unsubstituted, Ar is unsubstituted thienyl or phenyl, R R R R and R,are hydrogen, R is methyl and R is chlorine or fluorine.

References Cited UNITED STATES PATENTS 3,687,945 8/1972 Thiele et al.424-275 ALBERT T. MEYERS, Primary Examiner F. E. WADDELL, AssistantExaminer

